JP2019509885A - Modular continuous flow equipment - Google Patents

Abstract

  The present invention relates to a modular continuous flow apparatus for performing automated chemical multistage synthesis under continuous flow conditions. The apparatus includes a plurality of different types of continuous flow modules and a valve assembly that connects the continuous flow modules to each other in parallel or radially. This arrangement allows the chemical reaction sequence to be performed by pre-synthesizing and storing at the same time or synthesizing at least one intermediate product required in the main synthesis reaction sequence to obtain the final product. It becomes possible.

Description

Detailed Description of the Invention

  The present invention relates to a modular continuous flow apparatus for automated multistage chemical synthesis under continuous flow conditions. The apparatus comprises a plurality of different types of continuous flow modules and a valve assembly that connects the continuous flow modules to each other in parallel or radially. This arrangement allows the chemical reaction sequence to be performed by pre-synthesizing and interim storing at least one intermediate product, which is necessary in the main synthesis reaction sequence to obtain the final product, or synthesizing simultaneously. .

[Background of the invention]
As the number of available chemical transformations increases and new target compounds and classes can be reached, there is also an increasing demand for new target structures with new and desired properties. With an automated chemical system, it is possible to produce compounds quickly and in parallel. Since unmanned operation is possible, the cost of skilled research workers can be reduced, and the risk of exposure of research workers to hazardous substances can be minimized.

  Automated chemical systems are known in the prior art, many of which are limited to specific types of reactions and reaction sequences. For example, in an automatic solid-phase synthesizer that obtains peptides or oligonucleotides with high efficiency, limited steps such as activation / coupling / deprotection can be performed under limited conditions using a solid-phase carrier bound to a substrate. The reaction is repeated in a specific order.

  Furthermore, conventional synthesizers can only perform linear synthesis, and the desired target compound is built in steps from a single starting material. More efficient than linear synthesis is convergent synthesis, where individual precursors or intermediates are synthesized and then mixed to form a new intermediate or final target compound. . However, in convergent synthesis, it is necessary to store intermediates during multi-step synthesis and to perform reactions in parallel. On the other hand, many target compounds share a similar core structure that can be used to construct compound libraries from common key intermediates obtained by branched synthesis.

It would be desirable to provide a single synthesizer that can perform linear, convergent, and branching synthesis.
Burke et al. (Science 2015, 347, 1221-1226) teach a “synthesizer” that can sequentially couple various aryl halides or alkyl halides with protected boronic acids to yield various small molecules. Yes. This synthesizer is limited to only one repetitive set of reaction steps that can be repeated multiple times in the case of multi-step synthesis, ie reaction steps such as deprotection, coupling, purification.

  Ghislieri et al. (Angew. Chem. Int. Ed. 2015, 54, 678-682) and Nobuta / Xiao et al. (Chem. Commun., 2015, 51, 15133-15136) are divergent or convergent under continuous flow conditions. Disclosed is a chemical assembly system (CAS) that combines flow reactor modules in an interchangeable manner for conducting multi-step synthesis. Various small molecules can be obtained by changing the starting material, selecting different reagents, and changing the order of the flow reactor modules. Since a separate reactor module is required for each reaction stage, the reactor module cannot be used repeatedly in multi-stage synthesis. This system is limited to a small number of reactor modules due to practical reasons and the dispersion problems encountered. Furthermore, this system is limited to reagents that require the same conditions for conversion.

  Schwalbe et al. In EP 1174184 (B1) discloses an automated chemical processing system that includes a laminated reactor as a reaction module. The reaction can be carried out under continuous flow conditions. The reaction module is fixed in a straight line. In multi-step synthesis, a separate reaction module is required for each reaction step. If another multi-stage synthesis is performed, the system must be reconfigured. The disclosed laminated plate reactor is limited to specific reaction conditions, mainly at high temperatures.

  Automated flow reactor systems are already commercially available and can be purchased, for example, from Vaportec or Syris. However, these systems are very limited in terms of reagent supply. Only up to six different reagents are delivered, resulting in limiting the number of reactions and steps that can be performed. If you want to carry out more than three stages in succession, you must use multiple systems.

  U.S. Patent Application Publication No. 2003/156959 (A1) discloses a parallel arrangement of semi-continuous or continuous reactors, each reactor supplying one reagent from a reagent source container. In fluid communication. Reagents are pumped from a reagent source container to a supply distribution valve that selectively supplies the reagents to each reactor. The reactor is a small volume reactor and is integrated with the reactor block. The reaction mixture is removed from each reactor by a discharge tube to a waste reservoir, a sampling system for analysis, or other reaction system. In this system, the reaction product cannot be re-supplied to the feed distribution valve, so that a multi-step synthesis cannot be performed.

  German patent DE 102007028116 (B3) discloses a microfluidic system that mixes at least two starting materials in a similar reaction path under continuous flow conditions, the reaction paths being arranged in parallel. . The valve assembly is connected to four syringe pumps so that each starting material can be in fluid communication with each reaction path or mixing path via a distribution pipe so that the starting material flow rate remains constant. ing. Each valve has three positions: filling the syringe pump, applying a predetermined pressure to the filled syringe pump, and distributing the starting material to the reaction path or the mixing path via the distribution pipe. Even in this system, once the flow passes through the reaction path or the mixing path, it cannot be re-supplied to the valve assembly, so that a multi-step synthesis cannot be performed.

  Seeberger et al. (WO2013030247 (A1)) teaches a process and continuous flow reactor for the continuous preparation of the antimalarial drug artemisinin from dihydroartemisinic acid. In a single continuous flow reactor, three reactions are carried out to convert dihydroartemisinic acid to artemisinin. Photo-oxidation of dihydroartemisinic acid using singlet oxygen, cleavage reaction with acid, oxidation to artemisinin using triplet oxygen. This continuous flow reactor is easy to scale up, can provide a large specific surface area that ensures efficient irradiation, and can precisely control the reaction.

  Kopetzki et al. (WO2015007693 (A1)) discloses a process and continuous flow reactor for synthesizing dihydroartemisinin and artemisinin derivatives. In order to reduce artemisinin to obtain dihydroartemisinin, a column reactor having a special combination of a hydride reducing agent and at least one activator is required. The dihydroartemisinin can be further reacted to artemether, arteether, artesunate, arteric acid, and multiple other artemisinin derivatives in a single continuous flow reactor.

Thus, the prior art discloses continuous flow reactors for linear multi-stage reactions that implement a variety of different chemical reactions and purification methods.
However, further improved continuous flow reactors capable of performing convergent synthesis or simultaneously carrying out different reactions are not known in the prior art.

  Accordingly, it is desirable to provide a single multipurpose continuous flow apparatus for automated multistage synthesis. In particular, continuous, multi-stage synthesis of various small molecules can be performed automatically by the same continuous flow device without reorganizing or reconfiguring the continuous flow device to adapt the continuous flow device to the next reaction sequence. It is desirable to provide a flow device.

The object of the invention is solved by the teachings of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures and the examples of the application.
[Summary of Invention]
The present invention relates to a modular continuous flow apparatus for multi-stage synthesis,
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly.

  The continuous flow module is a reactor that performs various chemical reactions, such as compound oxidation, compound reduction, introduction of protecting groups, compound deprotection, esterification, etherification, saponification, cyclization, CC It is a reactor used for bond formation and the like. The continuous flow module can also be a reactor for intermediate product storage. As used herein, the term “intermediate product storage” refers to intermediate storage of intermediate products synthesized in the modular continuous flow apparatus of the present invention, since the intermediate products synthesize the final product, Used at any stage of the overall reaction procedure.

  According to the invention, the continuous flow modules are not directly connected to each other. This is because the order of modules is not defined, for example, the reaction is started in module 1, the reaction mixture is transferred to module 2 for purification, transferred to module 3 for the second stage, and module for workup. This is because the module is not defined in the defined reaction sequence such as being moved to 4 and moved to the module 5 for the third stage. The modular continuous flow device according to the present invention offers great advantages, any continuous flow module may be used first, any other may be used second, and others. Any of these may be used third. It is also possible to use module 5 first, followed by module 4, then module 1, module 3, and finally module 2. According to the present invention, continuous flow modules can be used in any order. Also, according to the present invention, since each continuous flow module is connected to the valve assembly, the continuous flow module can be used twice or multiple times in succession. Since each continuous flow module is connected to a valve assembly, the reaction mixture is after each reaction stage, each work-up stage, each purification stage, or each detection stage that must be performed on a particular continuous flow module. Always transported through the valve assembly. This transfers the reaction mixture through the valve assembly to any other continuous flow module. This allows the continuous flow module to be used in any order by the valve assembly. The only limitation is that the reaction mixture cannot be introduced into a continuous flow module where the reaction mixture is just derived. However, this does not mean that the two reaction steps cannot be carried out in the same continuous flow module. Of course, one reaction step can be performed in one continuous flow module, and further reaction steps can be performed without subsequent work-up or purification. Another limitation is that if two reactions are performed simultaneously, each reaction must be performed in one continuous flow module. Of course, it is not possible to perform two different reactions in one single continuous flow module. However, the modular continuous flow apparatus according to the invention may naturally comprise two or more similar continuous flow modules, for example a continuous flow module for photoreactions, whereby a reaction is carried out in the photoreactor 1. However, the other reaction can be carried out in the photoreactor 2.

  For this reason, the reaction mixture treated via the modular continuous flow device is most preferably a liquid, but may also be a gas. The reagent added to the liquid or gaseous reaction mixture is most preferably a reagent solution or a reagent gas such as oxygen, but may be a solid reagent in a powdered or pure liquid, or a viscous reagent.

  Thereby, it is essential to connect the continuous flow modules, so that the two reaction stages can be carried out simultaneously in two different continuous flow modules. This is not a series of continuous flow modules arranged in series, but in parallel or radially, and any one of the modular continuous flow devices can be placed in the first, second, final, or any other location. It is because it can be used in.

  The modular continuous flow apparatus of the present invention does not require rearrangement of the apparatus or rearrangement of the continuous flow module for various chemical reaction procedures and reaction sequences, and has adaptability and adaptability. For this reason, the modular continuous flow apparatus according to the present invention is designed as an apparatus for carrying out one specific reaction procedure, for example an apparatus for the synthesis of artemisinin as disclosed in WO2013030247 (A1) pamphlet. Rather, it is designed to allow a variety of different reaction sequences and chemical reactions to be performed in any order.

The modular continuous flow apparatus disclosed in the present invention is not limited to specific reaction procedures or specific reaction conditions, nor is it limited to the synthesis of a specific end product.
The present invention relates to a modular continuous flow apparatus for multi-stage synthesis,
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
The continuous flow modules are not directly connected to each other, but are connected to each other only via a valve assembly, and the continuous flow modules are connected to a reagent supply system via a valve assembly.

  Each continuous flow module is connected to another continuous flow module via a valve assembly, so that the continuous flow modules can be arranged in series or radially to provide flexibility. Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet (see FIG. 2a). Because of this connection, after performing a chemical step (which may also be a purification step) in a continuous flow module, the reaction solution derived from this continuous flow module is present in a modular continuous flow device. It can be reliably fed to any one of the other continuous flow modules.

  In the continuous flow apparatus of the prior art, there is no apparatus having such flexibility in performing various chemical reaction sequences. There is also no device capable of a convergent reaction sequence that requires the synthesis of intermediate products used for further reaction sequences during the defined reaction steps.

Detailed Description of the Invention
The present invention relates to an apparatus for performing multi-stage synthesis under continuous flow conditions.
The present invention relates to a modular continuous flow device for synthesis,
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly, thereby Connected to the flow module.

Alternatively, the present invention relates to a modular continuous flow device for multi-stage synthesis,
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
The continuous flow modules are not directly connected to each other, but are connected to each other only via a valve assembly, and the continuous flow modules are not directly connected to a reagent supply system and are connected via a valve assembly. Only connected to the reagent supply system.

  In the modular continuous flow device of the present invention, it is essential that each continuous flow module is connected to the valve assembly via at least one inlet and at least one outlet. Continuous flow modules are not directly connected to each other. Depending on the valve position, any connection between continuous flow modules via the valve assembly can be established. Thereby, for example, serial or parallel connections are possible.

  In one embodiment of the invention, parallel connection (also referred to as parallel arrangement) is obtained by indirectly connecting all continuous flow modules to each other via a valve assembly, and connecting all continuous flow modules in any order. Can be used in

The present invention relates to a modular continuous flow apparatus for multi-stage synthesis,
a) a plurality of continuous flow modules arranged in parallel;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly.

In other words, the present invention relates to a modular continuous flow apparatus for multistage synthesis,
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly, the continuous flow module Are arranged in parallel.

[Continuous flow module]
A continuous flow module is a flow reactor that performs a variety of different chemical reactions. The term “continuous flow module” also includes a flow reactor for purification and a flow reactor for storing intermediate products.

  The term “multiple continuous flow modules” refers to the presence of 3 or more, preferably 4, 5, 6, 7, 8, or 8 or more continuous flow modules. However, all continuous flow modules are flow reactors, preferably none of which are batch reactors. For this reason, all reactions are carried out in a continuous manner. Furthermore, most preferably all reactions are carried out under flow conditions. That is, the reaction is carried out continuously until the reaction mixture passes through the individual continuous flow modules and the complete reaction mixture passes through the individual continuous flow modules or at least the part of the continuous flow module where the reaction takes place.

A continuous flow module is, for example, a reaction vessel, column or tube in which a chemical reaction is carried out and is referred to herein as a flow reactor for different purposes.
The continuous flow module may be, for example, at least one heating flow reactor, at least one cooling flow reactor, at least one photochemical reaction flow reactor, at least one microwave irradiation flow reactor, at least It comprises or consists of a flow reactor for one electrochemical reaction, a flow reactor that is at least one double tube reactor, and a flow reactor that is at least one packed bed reactor. Each continuous flow module further comprises at least one inlet and at least one outlet in fluid communication with the valve assembly system.

  The heating reactor according to the present invention is preferably composed of a polytetrafluethylene (PTFE) tube reactor and a heating system, and the heating system is a furnace used in a conventional gas chromatographic analysis system. Or a heating system that achieves a temperature of 250 ° C. from ambient temperature. Alternatively, it may be a stainless steel reactor that realizes a temperature from ambient temperature to 350 ° C. In the heating reactor, all homogeneous reactions requiring high temperature treatment can be carried out. The cooling reactor preferably comprises a PTFE tube reactor and the PTFE tube reactor is placed in a cold bath controlled by an external chilling unit that can be cooled to -40 ° C. Alternatively, the PTFE tube reactor is cooled to -70 ° C by a dry ice heat exchanger. The cooling reactor may further comprise an additional inlet having a pre-cooling loop for directly mixing the reagents in the flow reactor. All homogeneous reactions that require cooling can be carried out in a cooling reactor. The photochemical reaction reactor is composed of a PTFE tube type reactor or a fluororesin (FEP) tube type reactor wound around either a medium pressure mercury (Hg) lamp or a light emitting diode (LED). The photochemical reactor can be heated or cooled. All homogeneous photochemical reactions can be carried out in a photochemical reaction reactor. The flow reactor for microwave irradiation includes a PTFE tube reactor and a microwave heating furnace. All homogeneous reactions requiring microwave irradiation can be carried out in a microwave irradiation reactor. In a double tube reactor, a homogeneous gas-liquid reaction can be carried out. The double tube reactor is composed of a tube surrounding a gas permeable inner tube through which a reagent passes. By controlling the gas pressure, the solution can be saturated without the need for a gas-liquid separator following the reactor. The double tube reactor can be placed in a temperature variable tank. In a packed bed reactor, a heterogeneous conversion can be performed in which the reagent is on a solid support or insoluble catalyst. The packed bed reactor can also be used to leach reagents into solution. The packed bed reactor is configured by arranging columns connected to a reagent flow through a switching valve. When the column is exhausted, it can be easily replaced. If necessary, the column can be further heated or irradiated with a light lamp. In a preferred embodiment according to the invention, the reactor can hold up to 15 ml.

  Preferably, but not limited to, the following reactions can be carried out by a continuous flow module that the modular continuous flow device according to the present invention may be equipped with. That is, oxidation, biphasic oxidation, epoxidation, olefination, aminolysis, hydrogenation, reduction, Michael addition, hydrolysis, introduction of protecting groups, cleavage reaction of protecting groups, singlet oxygen reaction, etherification, click reaction, Cleavage reactions with acids, esterification, saponification, photooxidation, nucleophilic substitution, radical substitution, carboxylic acid activation, Knebener gel reaction, Horner-Wadsworth-Emmons reaction, and Wittig reaction can be performed.

  The modular continuous flow device according to the present invention comprises 4 to 15 continuous flow modules, preferably 5 to 12 continuous flow modules, more preferably 6 to 10 continuous flow modules. Alternatively, the modular continuous flow device has at least 4, preferably at least 5, more preferably at least 6, even more preferably at least 7, even more preferably at least 8, even more preferably at least 9, Most preferably, it comprises at least 10 continuous flow modules.

  As described above, all the continuous flow modules are arranged in parallel and connected to the valve assembly via the inlet and outlet. The modular continuous flow device may further include modules that are not necessarily connected in parallel. Such a module may be a final product collector that will collect and store the final product, a detector module located anywhere in a modular continuous flow device, or a continuous flow module outlet and valve. It is a work-up module appropriately arranged between the assembly.

[Flow reactor for intermediate product storage]
In a preferred embodiment, one continuous flow module of the modular continuous flow device is a reactor for intermediate product storage. Intermediate products that are not continuously reacted in the next stage of the reaction sequence can be stored in a reactor for intermediate product storage, preferably under continuous flow conditions, until used in the reaction sequence. This intermediate product, also called “sub-route product”, is an intermediate product used in the synthesis main route, not the starting material, but the main route intermediate product (the sub-route formation in one stage of the main reaction sequence). Are treated as intermediate products that must be synthesized at the same time as they are synthesized.

Thus, a “main pathway intermediate product” refers to an intermediate product of a synthetic main pathway that is subjected to reaction with a sub pathway product.
The “synthetic main route” is a reaction sequence from the starting material to the final product.

A “synthesis sub-path” is a reaction sequence in which a sub-path product is synthesized, not a reaction sequence in which a final product is synthesized.
All other chemical compounds obtained in the reaction sequence are called “intermediate products” if the compound is not a by-pass product, is not a main-path intermediate product, and of course is not a final product.

  This intermediate product storage flow reactor offers significant advantages. By-pass products can be pre-prepared by the synthetic sub-route and into the flow reactor for intermediate product storage until the main route intermediate product and the sub-route product are reacted in the synthetic main route. Can be stored. The synthesis of the by-pass product is performed under continuous flow conditions. The by-pass product is preferably stored in a flow reactor for intermediate product storage under continuous flow conditions. The synthesis of the final product is also performed via the main synthesis route under continuous flow conditions. By synthesizing the final product in this manner, the continuous flow module can be used twice in the synthesis of the by-pass product and the synthesis of the final product.

  The flow reactor for storing at least one intermediate product has further great advantages. A flow reactor for storing intermediate products, not only by-pass products, but any intermediate products, including main-pass intermediate products, when increasing or decreasing the flow rate in the next continuous flow module during the next reaction stage Can be temporarily stored. If the amount of reaction solution to be processed is not changed and the flow rate is reduced, a portion of the amount that cannot be processed can be temporarily stored in a flow reactor for intermediate product storage. On the other hand, if the amount to be processed remains the same and the flow rate is increased in the next stage, i.e. if a larger amount of reaction solution is delivered to the next stage than delivered in the current stage, The reaction solution is not fed directly to the next continuous flow module. The resulting reaction solution is first accumulated in a flow reactor for storing intermediate products until the flow rate is increased enough to be processed through the next continuous flow module. None of the prior art devices can provide such advantages.

  The device according to the invention with a flow reactor for intermediate product storage is particularly useful when performing convergent chemical reaction sequences. FIG. 4 illustrates a convergent multi-step synthesis: a synthesis main route (19) having reaction steps 24a-24e, a synthesis sub-route 18a having two synthesis sub-routes, namely reaction steps 24f-24h, and a reaction. And a synthetic sub-path 18b having stages 24i and 24j. The first two reaction steps 24a and 24b of the synthesis route are performed simultaneously with the synthesis route 18b. Alternatively, the synthesis sub-path 18b is performed first and the sub-path product 23b is stored in the intermediate product storage module. The next reaction step 24c of the synthesis main route is carried out using the main route intermediate 22a and the sub route product 23b supplied from the intermediate product storage module. At the same time, the synthesis sub-path 18a is performed, the synthesis main path is further performed, and the sub-path product 23a is stored in a module for intermediate storage until the main path intermediate product 22b is obtained. In the final reaction stage 24e, the final product (25) is formed from the intermediate product 22b and the by-pass product 23a fed from the intermediate product storage flow reactor. FIG. 4 illustrates a convergent multi-stage synthesis including one synthesis main path and two synthesis sub-paths. In general, convergent multi-step synthesis may include only one synthesis sub-path, or may include two or more synthesis sub-paths.

  Convergent synthesis requires at least one major pathway intermediate product and at least one minor pathway product prepared by different synthetic pathways. However, if the reaction is carried out continuously, it is necessary to store the secondary pathway product until the main pathway intermediate product is synthesized. When the by-pass product is a reactive substance, or when it is sensitive to air or humidity and cannot be stored at room temperature, it is necessary to carry out reactions in parallel to shorten the storage time. That is, according to the apparatus of the present invention, a convergent multi-stage synthesis can be performed by performing a single reaction stage in parallel and storing the sub-path product.

  For this reason, the modular continuous flow device of the present invention comprising a flow reactor for storing intermediate products has significant advantages over prior art devices. That is, at least one intermediate product is synthesized by at least one reaction step, the intermediate product is stored, or the intermediate product is synthesized simultaneously with the main synthesis route, and the intermediate product, ie, pre-synthesized. Convergent chemical reaction sequences can be performed that require the intermediate product, stored in parallel or synthesized simultaneously, to be introduced into the reaction sequence whenever needed. As a result, according to the modular continuous flow apparatus according to the present invention, for example, the three-stage synthesis of the sub-path product by the synthesis sub-path and the four-stage synthesis of the main intermediate product by the synthesis main path are performed simultaneously or sequentially The by-pass product, stored or simultaneously synthesized, can be reacted with the synthesized main intermediate product to obtain further intermediate products, which further undergo two reaction steps. After that, it is converted into a final product. This complete reaction sequence, ie the synthesis main path and the synthesis sub-path, is carried out in a modular continuous flow apparatus in the form of a continuous flow. A modular continuous flow apparatus can be used for different reaction sequences by synthesizing the desired amount of final product without disassembling or relocating the continuous flow module and then using the continuous flow module in a different order. it can.

  The flow reactor for intermediate product storage is preferably a PTFE tube reactor that can accommodate at least 15 milliliters. The inlet and outlet of the flow reactor for intermediate product storage are connected to the valve assembly by two different fluid connections. A flow reactor for intermediate product storage can be used to store the by-pass product (23) in convergent multi-step synthesis. This by-pass product is later further transformed with the main-path intermediate product (22) and optionally other reagents. While storing intermediate products that are not by-pass products, it is time to adjust the reaction conditions of the continuous flow module. Adjustment time is given, particularly when one continuous flow module is used continuously under different conditions, for example at different flow rates or temperatures. Also, time is given when other reactions are performed in parallel. In addition, it takes time to maintain the equipment by replacing any defective columns in the packed bed reactor or replacing a defective continuous flow module without stopping the flow of reagents. Moreover, when the flow reactor (5) for storing intermediate products is a PTFE tube reactor, it may be used for the purpose of carrying out the reaction at ambient temperature. Modular continuous flow devices are implemented under continuous flow conditions, and because of the finite length of continuous flow modules, storage time may be limited. However, this restriction can be avoided when an infinite loop is arranged. For example, an infinite loop can be realized by linearly connecting two PTFE tube reactors through a multiport switching valve. The switching valve switches between two positions continuously at specified intervals, so that the reagent flow passes between the two PTFE tube reactors without changing the flow direction, and the solvent continuously loops Enter and exit the solvent. When continuous switching stops, the reagent flow exits an infinite loop.

As described above, in one embodiment of the present invention, the modular continuous flow device is
a) a plurality of continuous flow modules and a flow reactor for storing at least one intermediate product;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly, the continuous flow module Are arranged in parallel.

In an alternative embodiment of the invention, the modular continuous flow device is a device for convergent synthesis comprising:
a) a plurality of continuous flow modules for carrying out chemical reactions and at least one flow reactor for storing intermediate products;
b) a reagent supply system for supplying reagents;
c) a valve assembly for connecting the continuous flow modules to each other;
d) means for controlling the flow rate and / or pressure;
Each continuous flow module is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly, the continuous flow module Are arranged in parallel.

[Workup module]
In another embodiment according to the invention, the modular continuous flow device for convergent synthesis further comprises at least one work-up module (7). The work-up module is preferably composed of at least one liquid-liquid extraction device. The workup module inlet and the workup module outlet are preferably connected to the valve assembly via two different fluid connections. The liquid-liquid extraction device comprises an additional inlet for the aqueous phase that is mixed with the reagent stream before the two phases are separated, and a separator chip. The separator is composed of one inlet and two outlets. In the separator, a hydrophobic PTFE membrane separates the two phases. The organic phase passes through the membrane and is sent to the outlet of the workup module. The aqueous phase does not pass through the membrane and may be collected in a separate container or discarded as waste. According to the present invention, the reagent flow may pass through the work-up module after each reaction step or at the end of the reaction sequence. In order to increase the accuracy of the purification, the reagent flow may pass through the work-up module several times continuously. Of course, only one reagent flow can pass through the work-up module at a given time.

  The modular continuous flow apparatus according to the present invention preferably comprises two flow reactors for heating, two further continuous flow modules, a work-up module and a detector module. More preferably, the modular continuous flow device comprises one heating flow reactor, one cooling flow reactor, two further continuous flow modules, a work-up module, and a detector. Prepare. An even more preferred modular continuous flow apparatus comprises one heating flow reactor, one photoreaction flow reactor, one additional continuous flow module, a flow reactor for intermediate product storage, A work-up module; and a detector module. Particularly preferably, the modular continuous flow apparatus comprises one heating flow reactor, one cooling flow reactor, one photoreaction flow reactor and one intermediate product storage flow. Reactor, one flow reactor that is a double tube reactor, one flow reactor that is a packed bed reactor, one flow reactor for microwave irradiation, a work-up module, detection A reactor module and a purification flow reactor.

  The purification flow reactor is preferably a simulated moving bed chromatography comprising a plurality of reverse phase (RP-18) chromatography columns, a multi-port switching valve, a plurality of spare pumps, and a UV detector. (SMB) units are provided, but not limited thereto. The SMB chromatography unit allows continuous purification of the crude reaction product by arranging the columns in series and continuously switching the columns opposite to the eluent flow direction. For this reason, purification of the crude reaction product and regeneration of the used column can be achieved simultaneously.

  Since the flow reactor for purification is a continuous flow module and the flow reactor for storing intermediate products is also a continuous flow module, both modules are connected to the other in parallel via the valve assembly in the present invention. It is also arranged in parallel for all other continuous flow modules.

Thus, in one embodiment of the present invention, a modular continuous flow device for multi-stage synthesis is
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
e) a workup module;
Each continuous flow module and the work-up module are connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system is connected to the valve assembly .

[Parallel arrangement]
In addition to the connection between the reagent supply system and the valve assembly, according to the present invention, there are at least two separate fluid connections between each continuous flow module and the valve assembly. For this reason, the continuous flow modules are arranged in parallel.

  Preferably, each continuous flow module of the plurality of continuous flow modules is connected to the valve assembly. More preferably, each continuous flow module of the plurality of continuous flow modules is connected to a valve assembly having one inlet and one outlet.

  Each continuous flow module is individually connected to the valve assembly so that reagent flow is routed from one outlet port for each continuous flow module of the valve assembly to the inlet port of each continuous flow module. And from the outlet port of each continuous flow module to the inlet port for each continuous flow module of the valve assembly. Thus, the continuous flow modules are indirectly connected to each other via the valve assembly. Specifically, (a) the reagent flow can be directed from the reagent supply system to one continuous flow module via the valve assembly, and (b) the reagent flow is directed via the valve assembly. A continuous flow module can be directed to another continuous flow module; (c) via the valve assembly, a reagent flow can be directed from the continuous flow module to the same continuous flow module; and (d) a valve assembly. The reagent flow can be directed from the continuous flow module to the intermediate product storage flow reactor via (e) the valve assembly from the intermediate product storage flow reactor. (F) Via a valve assembly, reagent flow can be directed from one continuous flow module to the final product collector (31). Thus, one reagent stream is delivered continuously to different continuous flow modules or the same continuous flow module, or two or more reagent streams are delivered to two or more different continuous flow modules. Allows a multi-step synthesis to be performed, where one reagent stream is sent to a specific continuous flow module at a certain time. In other words, the valve assembly can be positioned to deliver the flow entering from any inlet port to any outlet port. However, only one flow can be sent to a specific outlet port at a given time.

  By using a valve assembly in combination with parallel flow modules arranged in parallel, the configuration can be highly adaptable to any multi-stage synthesis. Because there are a variety of different continuous flow modules, any practical conditions can be applied in reactions under continuous flow conditions. Since any continuous flow module can be used repeatedly, a longer synthesis can be synthesized without increasing the number of continuous flow modules. The above can also be achieved by controlling the flow rate of the solvent. Unlike the prior art, modular continuous flow devices can adjust the flow rate, i.e. residence time, for the later stages of a multi-stage sequence.

  In contrast to the prior art, it is possible to perform multiple multi-step synthesis in one fixed configuration. No reconfiguration of the device or expansion or removal of the continuous flow module is necessary. This is advantageous for multi-step synthesis consisting of four or more reaction steps, and shorter reaction sequences may be efficiently performed in another system.

[Valve assembly]
The valve assembly provided in the modular continuous flow device according to the present invention preferably includes a plurality of inlet ports, a plurality of outlet ports, and a plurality of port switching valves that connect the inlet ports and the outlet ports. And an intersection. Preferably, the valve assembly comprises at least one multiport switching valve comprising a mixer and / or splitter. By switching the switching valve, any inlet port is connected to any outlet port. Two different inlet ports cannot be connected to each other, and two different outlet ports cannot be connected to each other. The inlet port is a port through which fluid enters the valve assembly, and the outlet port is a port through which fluid exits the valve assembly. Only one connection can be established from one inlet port to one outlet port at the same time, but multiple connections can be established simultaneously between different inlet ports and different outlet ports. It is preferable that two or more different inlet ports and one outlet port cannot be connected. Similarly, it is preferable that connection cannot be made between one outlet port and two or more outlet ports. The valve assembly is in fluid communication with the reagent supply system and the continuous flow module. The movement of the reagent flow has a direction and this particular direction must not be reversed. For this reason, the flow of reagent from the reagent supply system is always directed towards the valve assembly. Thus, the reagent supply system is connected to the valve assembly via the inlet port. Each continuous flow module has a valve assembly via an outlet port (flow exits the valve assembly and enters the continuous flow module) and via an outlet port (flow from the continuous flow module enters the valve assembly). Connected to a solid. Thereby, the continuous flow modules are indirectly connected to each other via the valve assembly. Each continuous flow module is connected to itself through a valve assembly so that the flow can pass multiple times through a single continuous flow module. As described above, since the continuous flow modules are arranged in parallel, only one reagent flow can pass through one continuous flow module for a certain period of time. However, a large number of reagent streams may simultaneously pass through a large number of continuous flow modules, thereby allowing reactions to occur simultaneously.

  The valve assembly according to the present invention preferably further comprises an intersection for mixing different flows together. The intersection is preferably a three-way intersection connecting the two outlet ports and one inlet port of the valve assembly. A static in-line mixer may be arranged between the three-way intersection of the valve assembly and the inlet port to ensure mixed flow uniformity. Three flows from different continuous flow modules can be mixed by a three-way intersection, one flow from the continuous flow module and one flow from the reagent supply system can be mixed, and from the reagent supply system The two streams can be mixed. By directing the mixed flow to the intersection, more flow can be mixed continuously.

  The valve assembly according to the present invention preferably further comprises a flow splitter that splits one flow into two flows. The flow splitter may be fixed at a specific flow rate ratio or may be adjustable within a specific flow rate ratio range. The flow splitter has one inlet port connected to the outlet port of the valve assembly and two outlet ports connected to two different inlet ports of the valve assembly. The flow splitter splits the reagent stream delivered from the continuous flow module or reagent supply system into two reagent streams of the same component. The divided identical component streams are sent to two different continuous flow modules, for example two reactors, one reactor and one detector module.

  In one embodiment of the invention where one continuous flow module is a reactor for intermediate product storage, the valve assembly is employed so that two or more continuous flow modules can be used simultaneously. Therefore, the intermediate product of the synthesis main path is synthesized in the continuous flow module or part of the continuous flow module, and the intermediate product of the synthesis sub-path is synthesized in another continuous flow module or part of another continuous flow module. can do.

[Reagent supply system]
The reagent supply system of the modular continuous flow apparatus may be composed of one or more reagent supply subsystems. Each reagent supply system or reagent supply subsystem includes a plurality of reagent containers for storing each reagent and / or solvent, a reagent selector (9) that is a multi-port switching valve for accessing the reagent containers, and a reagent or And a solvent supply means (11). The supply means (11) is preferably a syringe or a syringe pump. The reagent container (17) may be pressurized and cooled if necessary. The system is not limited to liquid reagents. Solid or gaseous pure reagents can be dissolved first and then used as a solution. Each reagent container is individually fluidly connected to a reagent selector (9), which is fluidly connected to one or more supply means. For this reason, the reagent selector can send each reagent to one or more supply means. In addition, a container (10) containing a cleaning solution is also fluidly connected to the reagent selector. The reagent or solvent is transferred from the reagent container to the supply means via the arranged reagent selector. In order to prevent contamination, the line is washed with a cleaning solution from a container containing a cleaning solution before supplying the next reagent or solvent. The contaminated solvent and spent cleaning liquid are collected in a waste container (16). In a preferred embodiment, the reagent is transferred to the valve assembly via the injection loop (13). This connection is illustrated in FIG. 3a. The reagent is pumped into the apparatus by the solvent from the container (12) containing the solvent. Multiple injection loops may be activated, whereby multiple reagents or solvents are simultaneously supplied to the valve assembly of the device. With this form, the concentration of the reagent can also be controlled. Reagents may be stored as concentrated solutions in individual reagent containers. If the concentrated solution is transferred to the injection loop while having another solvent in another injection loop, mixing the two solutions before entering the valve assembly will differ from the concentration of the concentrated solution of the stored reagent. , A solution having the desired reagent concentration can be delivered to the valve assembly.

  Preferably, the reagent supply system can be connected to the valve assembly by one or more inlets and connected to at least one continuous flow module by one or more inlets. Continuous flow modules that require specific reagents to convert main path intermediate products, including starting materials, intermediate products, by-pass products, should be directly connected to the reagent supply system or valve assembly It is self-evident that the connection should be made without going through.

  The modular continuous flow device may comprise a filling station (FIG. 3b). The filling station is in fluid connection with a number of sample loops (14). Reagents are loaded from the reagent supply system (2) into the sample loop before being transferred to the valve assembly. Different reagents are stored in different sample loops. A solvent container (12) is connected to the filling station (15) and supplies the solvent in a continuous stream.

For this reason, the reagent supply system is preferably connected to the inlet port of the valve assembly via an injection loop or filling station.
[Continuity and convergence]
The modular continuous flow apparatus according to the present invention is an apparatus capable of performing multistage synthesis under continuous flow conditions. The modular continuous flow device according to the invention with a flow reactor for intermediate product storage is suitable for performing convergent synthesis under continuous flow conditions. For this reason, preferably the modular continuous flow device makes it possible to carry out convergent multi-stage synthesis under continuous flow conditions. Accordingly, in a preferred embodiment of the present invention, the modular continuous flow apparatus comprises one or more flow reactors for intermediate product storage.

  Usually, it is necessary to start with a predetermined volume of starting material solution in order to prepare a predetermined amount of final product. The starting material is then processed through a modular continuous flow apparatus in a continuous manner. It may be necessary to pre-synthesize one or more by-pass products that are stored in a flow reactor for storing one or more intermediate products.

  For this reason, “continuous” refers to starting with the volume of starting material solution required to obtain a given amount of final product and processing through a modular continuous flow device in a continuous manner. Synthesize a predetermined amount of final product.

  As used herein, a “continuous flow condition” is a stream or flow, the so-called “reagent flow” or “reagent flow” constantly passing through a modular continuous flow device, and modular It means that the desired end product is obtained in the end product collector at the outlet of the continuous flow device. The reagent stream may include starting materials, intermediate products, main path intermediate products, sub-path products, final products, reagents or solvents. “Continuous flow conditions” means that the reaction or reaction sequence is not carried out in a batch mode. While the stream passes through a modular continuous flow device, other streams containing reactants, reagents or solvents may join the initial stream. Also, one flow may be divided into two flows in a modular continuous flow device. As used herein, “continuous” defines that the flow is constantly moving. The flow rate may be constant during the reaction time, may vary, may increase and decrease continuously, or may be stopped for a short time. There is a direction of flow, the flow direction does not change, and it goes from the starting material to the final product. The synthesis can be carried out basically in two different ways under continuous flow conditions. One is a method in which the starting material constantly enters the apparatus and the final product is permanently recovered at the outlet of the apparatus without dividing the reaction mixture. The other is to make the reactants into defined flow segments. The segment has a finite volume and is surrounded by a solvent. The segments are pushed by the solvent and pass through a modular continuous flow device. To minimize segment dilution, the solvent is immiscible or additional immiscible solvents such as perfluorinated hydrocarbons are added to the boundaries of each segment. By using an immiscible solvent, it is also possible to reduce the dispersion effect that occurs especially in multi-step synthesis. Another way to minimize dilution and dispersion is to use a solvent as the carrier liquid in which the reactants dissolve. In-line mixers installed before and / or after each continuous flow module can be used to minimize dispersion and dilution. In addition, segmenting the continuous flow enables the use of powerful reagents such as hydrogen chloride and sulfuric acid. This is because system components are not permanently exposed to these reagents. With segmentation, the latter approach has higher throughput because multiple segments can be mixed and multiple segments can be injected in a serial or parallel fashion.

  Flow chemistry can generally apply extreme reaction conditions such as high temperature, pressure, microwave irradiation, etc. without concern for safety. Over the reaction time, reaction parameters such as temperature can be efficiently controlled and precisely adjusted, and higher yields and selectivity can be realized. Automating the continuous flow reaction makes it even easier to handle and allows unattended operation and experiment planning. Since the multi-stage reaction can be carried out continuously, it is effective for unstable, air-sensitive or toxic intermediates. In addition, important purification techniques such as chromatography, crystallization, or liquid-liquid extraction can be combined with the reaction process under continuous flow conditions.

  As used herein, “branched synthesis” or “diversification oriented synthesis” refers to a multi-step synthesis of at least two different end products synthesized from one common main pathway intermediate product. The final product generally has the same or similar core structure or skeleton that is part of a common main pathway intermediate product. A common main pathway intermediate is generally formed at the final stage of the multi-step synthesis, and diversification is achieved by reacting the common main pathway intermediate with different reagents and / or different reaction conditions.

[Fluid connection]
The invention also relates to a modular continuous flow device for multi-stage synthesis, the modular continuous flow device for multi-stage synthesis comprising:
a) a plurality of continuous flow modules;
b) a reagent supply system;
c) a valve assembly;
d) means for controlling the flow rate and / or pressure;
e) means for fluidly connecting the reagent supply system and the plurality of continuous flow modules to the valve assembly;
Each continuous flow module of the plurality of continuous flow modules is connected to the valve assembly by at least one inlet and at least one outlet, and the reagent supply system includes the valve Connected to the assembly.

  The fluid connection between the individual components of the modular continuous flow device is preferably realized by a flexible PTFE tube. The tube is connected to the valve and the inlet and outlet of each continuous flow module with a suitable device so that it is firmly fluidly connected and subjected to high pressure. The instrument is made of a corrosion resistant material. Alternatively, a stainless steel capillary may be used as the reactor coil for fluid connection, which improves heat exchange and allows higher temperatures / pressures to be achieved.

[Means for controlling flow velocity and / or pressure]
The modular continuous flow device according to the present invention further comprises means for controlling the flow rate and / or pressure. The means for controlling the flow rate and / or pressure is preferably a pressure regulator or a back pressure regulator. By limiting the pressure and / or back pressure, the flow rate can be adjusted. The pressure regulator is preferably installed in front of the valve assembly or at the outlet of each continuous flow module. The flow rate is controlled by limiting or reducing the high pressure created by adjusting the valve. The back pressure regulator is preferably installed at the outlet of the device, and it dampens the flow and limits the pressure (back pressure).

  The means for controlling the flow rate and / or pressure can be a means for performing both flow rate control and pressure control, a flow rate control means, or a pressure control means. However, the pressure usually increases as the flow rate increases, and the flow rate increases as the pressure increases.

  Since the reagent flow is divided into segments and the solvent is in between, the means for controlling the flow rate and / or pressure is preferably a pump that delivers the solvent, ie the reagent flow, to the modular continuous flow device. By manipulating the pump speed, the residence time of the reagent flow in the modular continuous flow device can be controlled. For example, if the second (or any subsequent stage) conversion requires a slower flow rate than the previous stage, the pumped solvent flow rate can be reduced.

  In the embodiment of the invention where one continuous flow module is a reactor for intermediate product storage, the opposite is also possible. If the flow rates of successive stages need to be greatly different, the reagent stream can be sent to a flow reactor for intermediate product storage, and the entire reagent stream can be sent to the previous flow reactor at the same flow rate. Thereafter, the flow rate of the intermediate product storage flow reactor can be adjusted by increasing or decreasing the flow rate. Once the correct flow rate is reached, the next continuous flow module can be entered. The flow rate can also be significantly reduced to allow time to change the conditions at the station or to change the packed bed reactor. The ability to slow (or speed up) the flow rate after the multi-stage sequence is unique compared to the prior art.

In order to use different flow rates and / or different pressures in each continuous flow module, means for controlling the flow rates and / or pressures are preferably used.
[Detector]
The modular continuous flow device may further comprise at least one detector (6) for monitoring the progress of the reaction. The detector is preferably an FTIR-spectrometer or UV-spectrometer, preferably suitable for continuous analysis of reagent streams. The detector has one inlet and one outlet connected to the valve assembly via two different fluid connections. However, only one reagent stream can pass through the detector for a period of time. By measuring the absorption of infrared (IR) or ultraviolet (UV), the detector can monitor the progress of the reaction after each reaction step and at the end of the reaction sequence, and further optimize the individual reaction steps can do.

[System controller]
The modular continuous flow device may further comprise at least one system controller (8) for controlling and monitoring chemical synthesis. The system controller is preferably for all components of the device, ie all multi-port switching valves, valve assemblies, pump systems, supply means, means for controlling the flow rate, each continuous flow module, for intermediate product storage Communication buses for components such as reactors, work-up modules and detectors. Furthermore, the system control apparatus is connected to a computer and may be controlled by a computer program. All components of the device are controlled by the system controller. The reaction may be performed automatically by a computer program. The reaction may be optimized by a computer program along with the detector.

[mixer]
The modular continuous flow device may further comprise a plurality of mixers. The mixer can reduce reagent flow dispersion, which is particularly necessary in multi-step synthesis. The mixer in the present invention is not limited, but is preferably a static in-line mixer, and the static in-line mixer is made of PTFE, glass, stainless steel, or polyvinyl chloride (PVC). By changing the movement of the reagent flow through the static mixer, the reagent flow becomes homogeneous. Since the static mixer is not composed of a drive unit, maintenance is almost unnecessary. The mixer may be installed as part of the fluid connection at the outlet of each continuous flow module, and may be part of the continuous flow module if necessary. A mixer may be installed between the reagent supply system and the valve assembly to mix the reagents before delivery to the continuous flow module.

Thus, the modular continuous flow device preferably further comprises a mixer preferably installed at the outlet of each continuous flow module to reduce the dispersion effect.
The modular continuous flow apparatus according to the invention comprises at least 4 reaction stages, preferably at least 5 reaction stages, more preferably at least 6 reaction stages, even more preferably at least 7 reaction stages, most preferably at least 8 reaction stages. It is an apparatus capable of carrying out multistage synthesis composed of reaction stage apparatuses. The maximum number of reaction steps in the multi-step synthesis is not limited by the apparatus.

  One important aspect of the modular continuous flow apparatus according to the present invention is that the reaction steps can be carried out simultaneously in different continuous flow modules. In the continuous flow module, a plurality of reactions can be carried out continuously, but only one reaction can be carried out at a given time. Therefore, different continuous flow modules are required to synthesize at the same time. The different continuous flow modules may be of different types or the same type (for example, one of the two heating reactors is set to 40 ° C. and the other is set to 80 ° C.). For example, when performing a three-stage convergent synthesis that inevitably consists of a two-stage main path and a one-stage sub-path, first the continuous flow modules with different two reaction stages simultaneously (eg photoreactor and heated reactor) Followed by a third reaction stage. The continuous flow modules I, II and III for the individual reactions (24a-24c) are set to be able to provide the required reaction conditions (eg heating, irradiation or cooling). Starting material for the main path (20a) is delivered from the reagent supply system directly to the valve assembly or through the sample loop of the filling station. Additional reagents are added to the starting material and mixed in the valve assembly. The valve assembly is set to fill the continuous flow module I with the reaction mixture. At the same time, the starting materials and reagents for the secondary path (20b) are provided in the same way from the reagent supply system and filled into the valve assembly. The valve assembly is set to direct the by-pass reaction mixture containing the starting material (20b) to the continuous flow module II without interrupting the flow through the continuous flow module I. During this particular period, the two reaction stages (24a) and (24b) are carried out in different continuous flow modules, namely I and II. Both reaction mixtures having by-products and main path intermediates enter the valve assembly again and merge at the valve assembly with the reagent delivered from the reagent supply system for the third reaction stage (24c). The reaction mixture is then charged from the valve assembly into the continuous flow module III, where a third reaction stage is performed to produce the final product. The crude end product (25) re-enters the valve assembly and is delivered from there to a module for work-up and purification, a detector for analysis, or an outlet of the device.

  Another important aspect of the modular continuous flow apparatus according to the present invention comprising a flow reactor for intermediate product storage is the ability to store by-pass products during convergent multi-step synthesis. In convergent multi-step synthesis, where each reaction step is performed sequentially but not simultaneously, and each synthesis sub-route is performed before the main synthesis route, storing the sub-route products and convergent synthesis Merging the by-pass product with the main-pass intermediate product for For example, if a convergent three-step synthesis is performed continuously, a by-pass product is first formed and stored. The main path intermediate product is then formed and merged with the stored sub-path product to undergo the reaction to obtain the final product. Specifically, the reagents for the starting material (20b) and synthesis sub-path (18) are delivered from the reagent supply system directly or through the sample loop of the filling station to the valve assembly. Continuous flow modules I, II and III are set to provide the reaction conditions required for the reactions (24a-24c). If the two reactions are performed continuously in the same continuous flow module, the reaction conditions for the second stage are set after the first reaction is complete. The valve assembly is positioned such that the reaction mixture for the first reaction is filled into the continuous flow module I. When the reaction is complete, the by-pass product (23) is again sent to the valve assembly, which sends the by-pass product to a continuous flow module for intermediate storage. In the continuous flow module for intermediate storage, the secondary path product stays until the main path intermediate product (22) is formed. Thus, the starting material (20a) and the reagents for the first reaction stage (24a) of the main route are delivered from the reagent supply system in the same manner and merged and mixed in the valve assembly. The valve assembly directs the reaction mixture to the continuous flow module II and a main path intermediate product (22) is formed. The main path intermediate product and the stored sub-path product are again transferred to the valve assembly where both compounds merge with the reagents for the third reaction stage (24c) and are loaded into the third continuous flow module III. The When the reaction is complete, the crude end product (25) re-enters the valve assembly and is delivered from there to further work-up, a module for purification, a detector for analysis, and a device outlet.

  In a preferred embodiment of the modular continuous flow device according to the invention with a flow reactor for intermediate product storage, the device is applied to the convergent synthesis of artemisinin derivative (30) under continuous flow conditions. Details of this are described in Example 4 and the synthesis is illustrated in FIG. In this particular embodiment, the modular continuous flow apparatus comprises a continuous flow module for photoreaction, a continuous flow module having a double tube reactor, a continuous flow module having a packed bed reactor, and an intermediate product. A continuous flow module for storage, a work-up module, a detector module, and a back pressure regulator are provided. The synthesis consists of four reaction steps, the main synthetic pathway starting from dihydroartemisinic acid is three steps long and proceeds to reduced dihydroartemisinin via artemisinin. Dihydroartemisinin is the main pathway intermediate and is subsequently transferred to the reaction of the alternative pathway product, esterified phenylpropionic acid, with N-hydroxysuccinimide. Artemisinin synthesis involves three reaction steps: photooxidation with singlet oxygen, cleavage reaction with acid, oxidation with triplet oxygen, which are referred to as a single step. The reagent supply system supplies starting materials and reagents necessary for all reaction steps.

[Example application of modular continuous flow device according to the invention for convergent multi-step synthesis of artemisinin derivatives]
For the formation of artemisinin, a solution of phenylpropionic acid, EDC and N-hydroxysuccinimide is used for dihydroartemisinic acid solution, trifluoroacetic acid (TFA) and photosensitizer dicyanoanthracene, and for the alternative pathway product. Starting from the main synthesis route, the dihydroartemisinic acid mixture is delivered from the reagent supply system to the valve assembly. The valve assembly is set to deliver the reaction mixture to a continuous flow module (saturated with oxygen) having a double tube reactor. The dihydroartemisinic acid solution is saturated with oxygen and transferred via a valve assembly to a continuous flow module for photoreaction. The photoreaction reactor is cooled before the oxygen-saturated dihydroartemisinic acid solution is introduced and irradiated. The reaction mixture is then transferred via a valve assembly to a module for intermediate product storage where the reaction mixture stays at room temperature and undergoes an acid cleavage reaction and a second oxidation. When the reaction is complete, the crude artemisinin solution is again sent to the valve assembly and transferred again to a continuous flow module having a double tube reactor and degassing the solution to remove excess oxygen. Returning to the valve assembly, the artemisinin solution merges with the ethanol provided from the reagent supply system and is transferred to a continuous flow module with a packed bed reactor for reduction of artemisinin to dihydroartemisinin. At the same time, the reagents for the starting materials and synthesis sub-paths, ie phenylpropionic acid, EDC, NHS, are delivered from the reagent supply system to the valve assembly. After mixing the reagents, the valve assembly is set to transfer the reaction mixture to a continuous flow module for intermediate product storage. In a continuous flow module for intermediate product storage, the reaction mixture stays at room temperature until the reaction is complete and the main pathway intermediate product dihydroartemisinin is prepared. When the formation of dihydroartemisinin is complete, the crude dihydroartemisinin solution is transferred through the valve assembly to the workup module for cleaning. The washed dihydroartemisinin solution and stored by-pass product are again sent to the valve assembly where they merge with the amine base supplied from the reagent supply system. This reaction mixture with the main path intermediate product and the sub-path product is later transferred to a continuous flow module for intermediate product storage where it remains at room temperature until the reaction is complete to the final product. The crude artemisinin derivative solution is finally transferred to the work-up module via the valve assembly and washed again. Artemisinin derivative is recovered at the discharge port of the apparatus.

In the schematic which shows the reagent supply system (2) of a prior art provided with a some reagent container (8), a reagent selector (9), a washing | cleaning-liquid container (10), a supply means (11), and an outlet. is there. Three continuous flow modules (1), a reagent supply system (2), a valve assembly (3), a final product collector (31), a continuous flow module (5) for storing intermediate products, 1 is a schematic diagram illustrating one embodiment of a modular continuous flow device comprising a detector module (6), a work-up module (7), and a system controller (8). Three continuous flow modules (1a, 1b, 1c), a reagent supply system (2), a valve assembly (3), a final product collector (31), a valve assembly and a final product collector ( 31) means for controlling the flow rate and / or pressure installed between, a continuous flow module (5) for intermediate product storage, a detector module (6), and a work-up module (7). And a system controller (8) is a schematic diagram illustrating one embodiment of a modular continuous flow device. FIG. 3 shows two embodiments for filling reagents and / or solvents from the reagent supply system (2) to the valve assembly (3), and FIG. 3a shows that the reagent supply system is routed through an injection loop (13). Connected to the valve assembly. Since there is a port for the solvent from the solvent container (12) and a port for the waste to the waste container (16), after each reagent is injected, the line is surely washed to prevent contamination Can do. FIG. 3 shows two embodiments for filling reagents and / or solvents from the reagent supply system (2) to the valve assembly (3), and FIG. 3b shows that two reagent supplies are filled in the filling station (15). FIG. 2 illustrates the settings connected to the valve assembly via. The filling station comprises two sample loops (14) that can be filled either from the same reagent supply system or from different reagent supply systems. The reagent may be stored in the sample before being introduced into the valve assembly (3). Additional ports for solvent containers (12) and waste containers (16) ensure that the lines and filling stations can be cleaned after each reagent is filled to prevent contamination. A configuration of convergent multistage synthesis is shown. The synthesis can be divided into a synthesis main route (19) and in this example two synthesis sub-routes (18a, 18b). The main synthesis route (19) is selected by including the final product (25) and having the reaction step sequence of the longest reaction step. The synthetic sub-path (18a, 18b) does not reach the final product (25), but always reaches the sub-path product (23a, 23b). 1 illustrates a representative example of a modular continuous flow apparatus according to the present invention. The legend of FIG. 5 is as follows. Shown is a convergent multi-step synthesis of rufenamide (28), starting from 2,6-difluorotoluene and methyl propiolate and going through 4 steps under continuous flow conditions. Shown is a convergent multi-step synthesis of N-Fmoc protected pregabalin (29), going through 7 steps under continuous flow conditions from triethyl phosphonoacetate and isopentanol. The convergent synthesis of the artemisinin derivative (30) is shown, starting from dihydroartemisinic acid and phenylpropionic acid and going through 4 stages.

FIG. 5 illustrates a typical example of a modular continuous flow device according to the present invention. The legend of FIG. 5 is as follows.

  The following examples illustrate preferred embodiments of the present invention. It will be understood by those skilled in the art that the technology disclosed in the embodiments follows the expression technology discovered by the inventor in order to function well in practicing the present invention, and can be considered to constitute a preferable form. It should be. However, it will be appreciated that changes may be made in the particular embodiments disclosed and similar or similar results may be obtained under the present disclosure without departing from the spirit and scope of the present invention. Should be understood by the contractor.

  Further modifications and alternative embodiments in various aspects of the invention will be apparent to those skilled in the art in view of this specification. In addition, this specification is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It should be understood that the forms of the invention shown and described herein are to be taken as examples of embodiments. Elements and materials may be substituted for those described and described herein, some of the steps and steps may be altered, and certain features of the invention may be utilized independently. Well, all will be apparent to those skilled in the art after enjoying the advantages of the present invention herein. The elements described herein may be modified without departing from the spirit and scope of the invention as described in the following claims.

[Example 1]
Typical modular continuous flow setup for automated convergent multi-step synthesis (Figure 5).

  The settings described herein are shown in FIG. The modular continuous flow apparatus according to the present invention comprises a reagent supply system (2), a valve assembly (3), a means (27) for controlling flow rate and pressure in a pump manner, and a plurality of continuous flow modules (1) ( FIG. 5 shows as one module), a flow reactor (5) for storing intermediate products, a workup module (7), a detector module (6), and a final product collector (31). And a system control device (8). The reagent supply system comprises four reagent containers (17a, 17b, 17c, 17d), which are connected to a reagent selector (9). Liquid or dissolved reagent is supplied by a syringe pump (11) and filled into individual sample loops (14a, 14b) of the filling station (15). After each filling, the line is flushed with solvent from the solvent container (12) to prevent contamination. The pressure is established by means (4) for controlling the flow rate and pressure of the pump (27) system. A flow reactor for carrying out the reaction is selected with the aid of a valve assembly, and the flow reactor is set to carry out the desired reaction conditions, ie temperature, pressure, irradiation. The reagent is then charged into the flow reactor in which the first reaction stage takes place with the help of the filling station (15). During the first reaction, the reagents for the second reaction stage are charged from the reagent supply system to the valve assembly and from there to another flow reactor. Both reaction mixtures are then sent again to the valve assembly (3) where they are mixed with additional reagents and transferred to another flow reactor for the third reaction stage. Once the reaction is complete, the mixture is then mixed with additional reagents for various other reactions, or a work-up module (7) in the form of a liquid-liquid extraction device or an in-line flow IR detector. To the detector module (6) which is in the form. When the synthesis is complete, the final product is recovered in the final product collector (31). The entire synthesis is performed automatically until the desired compound is obtained in the desired yield. All components of the device are controlled by dedicated process control software from a computer (26) connected to the detector module (6) and the system controller (8) and can be controlled in real time by the system controller (8). It is.

[Example 2]
Convergent synthesis of rufinamide (28) using a modular continuous flow apparatus according to the present invention (Figure 6).

A solution containing 2,6-difluorotoluene (128 mg, 1 mmol) and AIBN (azobisisobutyronitrile, 2 mg) in 1 mL of ethyl acetate and NBS (N-bromosuccinimide, 178 mg, 1 mmol) in 1 mL of ethyl acetate Containing solutions are prepared and placed in individual reagent containers of the reagent supply system. The continuous flow module for heating is set to 60 ° C. Ethyl acetate is washed away through the apparatus. The reagent is then transferred from the reagent supply system to the valve assembly and mixed. The valve assembly is configured to transfer the reagent to the heating continuous flow module. The mixed reagent is introduced into a continuous flow module for heating. The valve assembly is configured to transfer the crude difluorobenzyl bromide solution from the heating continuous flow module to the cleaning workup module. The work-up module is filled with a saturated aqueous NaHCO ₃ solution. When the liquid-liquid extraction is complete, the difluorobenzyl bromide solution is again transferred to the valve assembly and prepared sodium azide (85 mg, 1.3 mmol) in dimethyl sulfoxide (DMSO) solution 2 delivered from the reagent supply system. Mix with 6 mL. The stream is then introduced into a module for intermediate product storage. At the same time, methyl propiolate (126 mg, 1.5 mmol) and 25 wt% aqueous ammonia solution stored in the reagent supply system are mixed and transferred to a cooling continuous flow module set to 0 ° C. in advance. The mixture stays in the cooling continuous flow module for 5 minutes and is then returned to the valve assembly and mixed with the stored intermediate. The mixed reagent stream is then transferred to a continuous flow module equipped with copper turnings and equipped with a packed bed reactor heated to 110 ° C. After the last reaction stage, the flow again enters the valve assembly and is sent to the outlet located behind the back pressure regulator, where the product rufinamide (28) is recovered.

[Example 3]
Multi-step synthesis of N-Fmoc protected pregabalin (29) using a modular continuous flow apparatus according to the present invention (FIG. 7).

  The above compound N-Fmoc protected pregabalin is synthesized in 7 steps from triethyl phosphonoacetate and isopentanol. In addition to the valve assembly and reagent supply system, this modular continuous flow device for multi-stage synthesis includes a continuous flow module for heating, a continuous flow module for cooling, a module for storing intermediate products, and a plurality of modules. A work-up module composed of a liquid-liquid extraction device capable of extraction, a continuous flow module for gas-liquid reaction, and a continuous flow module including a packed bed reactor. Further, each continuous flow module outlet is provided with a static in-line mixer for reducing the dispersion problem.

A solution containing triethyl phosphonoacetate (224 mg, 1 mmol) in 1 mL toluene / MeOH (4: 1 v / v), a solution containing KOtBu (112 mg, 1 mmol) in 1 mL toluene / MeOH, and isopentanol in 1 mL toluene. Solution containing (88 mg, 1 mmol) is prepared and placed into individual reagent containers of the reagent supply system. The reagent supply system also has a solution containing sodium hypochlorite (93 mg, 1.25 mmol) and potassium bromide (12 mg, 0.1 mmol) in 4 mL of water. Toluene is washed away through the apparatus. The phosphonoacetic acid triethyl solution and the KOtBu solution are transferred from the reagent supply system to the valve assembly and mixed. The valve assembly is set to transfer the reaction mixture to an intermediate product storage module where triethyl potassium phosphonoacetate stays for 30 minutes. Meanwhile, the cooling continuous flow module is set to 0 ° C. The solution containing isopentanol and NaOCl is transferred, mixed and transferred to a cooling continuous flow module through a positioned valve assembly. The reaction mixture stays at 0 ° C. for 25 minutes and is then transferred through the valve assembly to the workup module. In the work-up module, the crude isovaleric aldehyde solution is washed with a saturated aqueous NaHCO ₃ solution. After phase separation has taken place, the isovaleric aldehyde solution is again transferred to the valve assembly where it is mixed with the potassium ethyl phosphonoacetate solution stored in a continuous flow module for intermediate product storage. The mixed reaction mixture is then again passed through a continuous flow module for intermediate product storage for 10 minutes and then washed with 1M HCl solution in the workup module. A solution of nitromethane (92 mg, 1.5 mmol) and tetrabutylammonium fluoride (261 mg, 1 mmol) in 1 mL of THF is delivered from the reagent supply system and merged with ethyl 2-hexenoate. The heating continuous flow module is heated to 50 ° C. and the mixed reaction mixture is transferred to the heating continuous flow module and stays for 60 minutes. The crude reaction mixture is then passed through a work-up module through a valve assembly and washed with 1M HCl solution. After phase separation, the mixture is mixed with a solution of lithium hydroxide (36 mg, 1.5 mmol) in 1 mL of water and transferred again to the heating continuous flow module, which is still set at 50 ° C. The mixed reagent stays for 60 minutes and is then washed with 1M HCl solution in the workup module. The aqueous phase is extracted with toluene. The toluene extract merges with the washed reagent stream and is transferred via a valve assembly to a continuous flow module for gas-liquid reactions consisting of a double tube reactor. The double tube reactor is saturated with hydrogen gas. When the mixture is transferred to a double tube reactor, the nitrocarboxylic acid stream is saturated with hydrogen. The hydrogen saturated nitrocarboxylic acid solution is then transferred to a continuous flow module having a packed bed reactor with a palladium on carbon (Pd / C) column. The pregabalin solution is then mixed in the valve assembly with a solution containing Fmoc-Cl (259 mg, 1 mmol) and N-methylmorpholine (101 mg, 1 mmol) in 2 mL of THF supplied from the reagent supply system. Subsequently, the reaction mixture is passed through a module for intermediate product storage for 20 minutes before being washed with saturated aqueous NaHCO ₃ in the work-up module. Finally, N-Fmoc protected pregabalin (29) is recovered at the outlet of the device located behind the back pressure regulator.

[Example 4]
Convergent synthesis of artemisinin derivative (30) using modular continuous flow apparatus according to the present invention (FIG. 8)

A solution containing dihydroartemisinic acid (236 mg, 1 mmol), TFA (57 mg, 0.5 mmol) and dicyanoanthracene (1.2 mg, 0.005 mmol) in 2 mL of toluene is prepared and placed in individual reagent containers of the reagent supply system. It is done. In addition, a solution containing phenylpropionic acid (150 mg, 1 mmol) in 1 mL THF, a solution containing EDC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 155 mg, 1 mmol) in 1 mL THF, 1 mL Solutions containing N-hydroxysuccinimide (115 mg, 1 mmol) in THF are prepared and stored in individual reagent containers of the reagent supply system. These solutions (phenylpropionic acid, EDC and NHS) are fed continuously from the reagent supply system and mixed. The reaction mixture is passed through an intermediate product storage module for 30 minutes. Meanwhile, the continuous flow module for gas-liquid reaction composed of a double tube reactor is saturated with oxygen. The valve assembly is set so that the dihydroartemisinic acid solution injected from the reagent supply system is transferred to the dual tube reactor. The dihydroartemisinic acid solution is saturated with oxygen and passed through a continuous flow module for photoreaction through a valve assembly. The continuous flow module for photoreaction is composed of an FEP tube surrounding an LED module and an electric chiller. The reactor is cooled to −20 ° C., after which an oxygen saturated dihydroartemisinic acid solution is introduced and irradiated for 3 minutes. The reaction mixture is then transferred to an intermediate product storage module and stays at room temperature for 8 minutes. Excess oxygen is removed by passing the crude artemisinin solution again through a continuous flow module for gas-liquid reaction set at reduced pressure. In the valve assembly, 0.27 mL of ethanol is added to the artemisinin solution and then transferred to a continuous flow module equipped with a packed bed reactor. The packed bed reactor is equipped with a column packed with a mixture of 650 mg Celite, 650 mg lithium carbonate (Li ₂ CO ₃ ), 650 mg sodium borohydride (NaBH ₄ ) and 520 mg lithium chloride (LiCl). The reaction mixture is passed through the column at a flow rate of 0.2 mL / min and then washed with water in the workup module. The washed dihydroartemisinin solution is then combined with the stored phenylpropionic acid active ester solution and NEt ₃ (0.1 mL, 0.73 mmol) and mixed. It is then passed through an intermediate product storage module where it stays for 25 minutes. The crude reaction solution is then washed with 1M HCl solution in the work-up module, and the organic phase containing the final product is recovered at the outlet of the modular continuous flow device located behind the back pressure regulator.

DESCRIPTION OF SYMBOLS 1 ... Continuous flow module, 2 ... Reagent supply system, 3 ... Valve assembly, 4 ... Means to control flow rate and / or pressure, 5 ... Flow reactor for intermediate product storage, 6 ... Detector module, 7 ... Workup module, 8 ... system controller, 9 ... reagent selector, 10 ... cleaning solution container, 11 ... supply means, 12 ... solvent container, 13 ... injection loop, 14 ... sample loop, 15 ... filling station 16 ... waste container, DESCRIPTION OF SYMBOLS 17 ... Reagent container, 18 ... Synthesis sub route, 19 ... Synthesis main route, 20 ... Starting material, 21 ... Intermediate product, 22 ... Main route intermediate product, 23 ... Sub route product, 24 ... Reaction stage, 25 ... Final product, 26 ... computer, 27 ... pump, 28 ... rufinamide, 29 ... N-Fmoc protected pregabalin, 30 ... artemisinin derivative, 31 ... final product collector.

Claims (14)

A modular continuous flow device for multi-stage synthesis,
a) a plurality of continuous flow modules (1);
b) a reagent supply system (2);
c) a valve assembly (3);
d) means (4) for controlling the flow rate and / or pressure;
Each continuous flow module (1) is connected to the valve assembly (3) by at least one inlet and at least one outlet;
The reagent supply system (2) is connected to the valve assembly (3);
Modular continuous flow device.   The modular continuous flow device according to claim 1, wherein the continuous flow module (1) further comprises a flow reactor (5) for storing at least one intermediate product.   The continuous flow module (1) comprises at least one heating flow reactor, at least one cooling flow reactor, at least one photochemical reaction flow reactor, and at least one microwave irradiation. A flow reactor for at least one electrochemical reaction, a flow reactor for at least one double tube reactor, and a flow reactor for at least one packed bed reactor. The modular continuous flow device of claim 1, comprising:   The modular continuous flow device according to any one of claims 1 to 3, wherein the continuous flow module (1) is arranged in parallel.   5. The modular continuous flow device according to claim 1, wherein the continuous flow modules (1) are connected to each other only via a valve assembly (3).   The reagent supply system (2) is connected to the valve assembly (3) by one or more inlets and is connectable to at least one continuous flow module (1) by one or more inlets. Item 6. The modular continuous flow device according to any one of Items 1 to 5.   The modular continuous flow device according to any one of claims 1 to 6, wherein any continuous flow module (1) is not directly connected to any other continuous flow module.   The modular continuous flow device according to claim 3, wherein said at least one intermediate product storage flow reactor (5) stores said intermediate product (21) in a closed circuit (under flow conditions). .   9. The means (4) for controlling the flow rate and / or pressure is adapted to use different flow rates and / or different pressures in each continuous flow module (1). The modular continuous flow device described.   The modular continuous flow device according to any of the preceding claims, further comprising at least one work-up module (7).   11. The modular continuous flow device according to any one of the preceding claims, wherein the valve assembly (3) comprises at least one multiport switching valve with a mixer and / or splitter.   12. The reagent supply system (2) according to any one of the preceding claims, wherein the reagent supply system (2) is connected to an inlet port of the valve assembly (3) via an injection loop (13) or a filling station (15). The modular continuous flow device described.   The modular continuous flow device according to any one of claims 1 to 12, further comprising a mixer installed at the outlet of each continuous flow module (1) to reduce the dispersion effect.   One inlet further comprising at least one detector (6) for monitoring the progress of the reaction, wherein the at least one detector is connected to the valve assembly (3) via two different fluid connections The modular continuous flow device according to claim 1, wherein the modular continuous flow device has one outlet and one outlet.